An increasing number of implantable biodegradable polymeric drug systems are now in clinical use or undergoing experimental and clinical investigations for diverse therapeutic applications. It is proposed to use copolymers of lactic and glycolic acid as carrier materials for the controlled release of multiple antimycobacterial drugs for therapy of tuberculosis with the desire of delivering the entire regimen in one or few doses. By doing so, it will be possible to solve the patients' compliance problem, which is the most serious stumbling block for successful outcome of chemotherapy. The work proposed addresses specifically some of the important conceptual and technical issues that must be considered in the development of implantable or injectable biodegradable polymeric systems for use as a single initial injection of multiple drugs for the effective long term treatment of tuberculosis. The systems proposed offer considerable promise for achieving multiphasic or "pulsed" controlled release of several (multiply drug) accepted chemotherapeutic agents. The main studies of this grant will deal with standardization of the biodegradable polymer preparations containing the antituberculosis drugs, the bioavailability of these preparations resulting with achievable serum and tissue levels in vivo of the antituberculosis drugs, short and long term toxicity, and more importantly, the in vitro and in vivo activity in experimental tuberculosis. The specific aims of this grant are: 1) to synthesize and purify copolymers of lactic an glycolic acids containing the antituberculosis drugs, 2) to study the pharmacokinetics and bioavailability for prolonged periods after administration of these drugs through the polymers to different animal species, 3) to assess the in vitro activity of these polymers containing antituberculosis drugs, 4) to assess the in vivo chemotherapeutic activity of antituberculosis drugs in experimental murine model, and 5) to investigate the changes in the host, especially the liver enzymes and other related conditions leading to hepatitis and other complications.